The para- and/or meta-substituted cyanophenylalanine derivatives are important intermediate in medicinal chemistry. Particularly, it acts as a very useful intermediate for preparing the thrombin inhibitor LB30057 which has been recently developed by LG Chemical Ltd. as a selective and orally-administered thrombin inhibitor. Therefore, establishment of the effective manufacturing process thereof is very important for preparing LB30057. ##STR6##
Further, para- and/or meta-substituted cyanophenylalanine derivatives have been used as a key intermediate in the preparation of the existing thrombin inhibitor CRC 220(Terahedron, 1995, 51, 12047) and GPIIb/IIIa receptor antagonist(J. Med. Chem. 1996, 39, 1372).
For the synthesis of para- and/or meta-substituted cyanophenylalanine derivatives, catalytic asymmetric hydrogenation (Terahedron, 1995, 51, 12047), alkylation of the enolate of glycine derivative(J. Chem. Soc. Perkin Trans 1, 1996, 645 and J. Am. Chem. Soc. 1997, 119, 656) have been disclosed. These methods, however, have some drawbacks therewith that adeprotection during the synthesis is not easy and large scale production can hardly be achieved thereby.
The present inventors have already developed a process for preparation of said intermediate based on a cyanation reaction using a palladium catalyst as a result of extensive study. Then, we filed a patent application claiming the invention(Korean Patent Application No. 97-41254).
Under such a technical situation, the present inventors have constantly tried to economically and conveniently prepare the useful medicinal intermediate, compound of formula (1) above. During the tries, unexpectedly, we found that such a purpose can be accomplished by reacting the compound of formula (2) with a cyanide in the presence of a nickel catalyst, and then completed the present invention.